1. Field of the Invention
The present invention relates generally to the fields of cell biology, pathology and intracellular signaling. More particularly, it concerns methods and compositions relating to modified Toll-like receptor 2 ligands that inhibit inflammation to a broad array of pro-inflammatory stimuli by usurping TLR2 and activating peroxisome proliferator-activated receptors.
2. Description of Related Art
Toll-like receptors (TLRs) are important sentinel receptors of the immune system. Upon ligand binding, these receptors initiate receptor-specific recruitment of a family of TIR-domain-containing adaptor proteins, which further initiate signaling cascades that culminate in the activation of cell-type-specific, and receptor/ligand-specific inflammatory responses (Brikos and O'Neill, 2008; Beutler, 2009; Manicassamy and Pulendran, 2009). In particular, TLR2 forms heterodimers with either TLR1 or 6 in order to initiate inflammatory responses upon stimulation with a wide variety of microbial-derived ligands (Ozinsky et al., 2000; Zahringer et al., 2008). A unifying feature of many of these TLR2 ligands is their acylation status, where acylation patterns impart specificity to receptor-ligand interactions; di-acylated ligands are recognized by TLR2/6 heterodimers and tri-acylated ligands are recognized by TLR2/1 heterodimers (Kang et al., 2009; Jin et al., 2007). Principal among these ligands are acylated lipopeptides derived from bacteria, however other acylated bacterial components, such as the gram-positive bacterial cell wall component lipoteichoic acid (LTA), are also recognized by TLR2 (Schroder et al., 2003).
TLR-induced activation of acute inflammatory responses is ultimately responsible for the eradication of infectious agents, in part through the recruitment of polymorphonuclear neutrophils from the bloodstream into the affected tissue. This recruitment follows a well-characterized cascade of successive steps, reviewed in refs (Ley et al., 2007; Petri et al., 2008) that allow the neutrophils to deal with the offending microbes through the activities of proteases, bactericidal peptides and reactive intermediates. In addition to the host-protective role that these cells play in the immune response, excessive or inappropriate neutrophil recruitment results in significant pathophysiology and morbidity (Jaeschke and Hasegawa, 2006; Zemans et al., 2009; Brown and Mayer, 2007).